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Kidney Week

Abstract: PO2513

Renoprotective Effects of Soluble Guanylate Cyclase (sGC) Activation vs. ACE Inhibition in a CKD Model with Volume/Salt-Dependent Hypertension

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Griffin, Karen A., Edward Hines Junior VA Hospital, Hines, Illinois, United States
  • Sethupathi, Perianna, Loyola University Health System, Maywood, Illinois, United States
  • Sheikh, Shehla, Edward Hines Junior VA Hospital, Hines, Illinois, United States
  • Williamson, Geoffrey A., Illinois Institute of Technology, Chicago, Illinois, United States
  • Kraehling, Jan R., Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Benardeau, Agnes M., Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Eitner, Frank, Bayer AG, Leverkusen, Nordrhein-Westfalen, Germany
  • Bidani, Anil K., Edward Hines Junior VA Hospital, Hines, Illinois, United States
Background

BP control using renin-angiotensin system (RAS) blockade is the current standard of care for CKD. However, outcomes remain suboptimal in part because adequate BP reductions are difficult to achieve in the volume expanded CKD states with RAS blockade even with additional antihypertensives. Given that endothelial dysfunction and/or NO loss accelerate the progression of both diabetic and non-diabetic CKD, sGC activators represent potential novel therapeutic interventions in CKD.

Methods

Two weeks after 3/4 nephrectomy and instrumentation for chronic BP radiotelemetry, male Sprague-Dawley rats were switched to a 4% NaCl diet after proteinuria measurements. After 2 weeks on the 4% NaCl diet and repeat proteinuria measurements, the rats started receiving vehicle only (5 ml/kg), the ACE inhibitor, enalapril (50 mg/kg), the sGC activator (BR-11257) (10 mg/kg), or the combination of BR11257 + enalapril by daily gavage. After 6 weeks of therapy and final proteinuria measurements, the rats were sacrificed for a blinded histologic assessment of % glomerulosclerosis (GS).

Results

In this CKD model with volume (salt) dependent hypertension (HTN), BR-11257 alone or in combination with enalapril but not enalapril alone, significantly lowered BP, ameliorated proteinuria and reduced the development of GS (Table). Linear regression analysis showed a strong correlation between individual systolic BP (SBP) and % GS (r=0.69, n=63, p < 0.0001), without a significant difference in the slope of the relationship (0.3 + 0.04) between treatment groups.

Conclusion

These data strongly support the therapeutic potential of sGC activators alone or in combination with RAS blockade in hypertensive and proteinuric CKD states.

GroupBefore Treatment (2 weeks)
4% NaCl diet
On Treatment (6 weeks)
4% NaCl diet
GS
(n)Average SBP
(mmHg)
Proteinuria
(mg/24 hours)
Average SBP
(mmHg)
Final Proteinuria
(mg/24 hours)
%
Vehicle
(n=16)
142.2
±
2.4
26.8
±
5.3
170.4
±
4.3
77.6
±
13.5
11.8
±
3.0
Enalapril
(n=17)
143.9
±
4.2
44.0
±
10.6
168.2
±
6.4
99.8
±
19.8
15.9
±
3.2
BR 11257
(n=15)
143.1
±
3.5
40.0
±
10.0
140.4*δ
±
4.6
42.6*δ
±
10.7
7.1
±
1.8
BR 11257 + Enalapril
(n=15)
149.2
±
2.9
35.2
±
7.5
133.1*δ
±
2.6
29.4*δ
±
7.8
3.2*δ
±
1.4

*p < 0.01 maximum vs. vehicle δ; p < 0.05 maximum vs. compound D

Funding

  • Commercial Support